Olanzapine 5 mg plus standard antiemetic therapy for the prevention of chemotherapy-induced nausea and vomiting (J-FORCE): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial

Summary

Background

Olanzapine 10 mg added to standard antiemetic therapy including aprepitant, palonosetron, and dexamethasone has been recommended for the prevention of chemotherapy-induced nausea and vomiting. Guidelines suggest that a dose reduction to 5 mg should be considered to prevent sedation. In several phase 2 studies, olanzapine 5 mg has shown equivalent activity to olanzapine 10 mg and a favourable safety profile in relation to somnolence. We evaluated the efficacy of olanzapine 5 mg combined with standard antiemetic therapy for the prevention of chemotherapy-induced nausea and vomiting caused by cisplatin-based chemotherapy.

Methods

This was a randomised, double-blind, placebo-controlled, phase 3 study to evaluate the efficacy of olanzapine 5 mg with triplet-combination antiemetic therapy done in 26 hospitals in Japan. Key inclusion criteria were patients with a malignant tumour (excluding those with a haemopoietic malignancy) who were scheduled to be treated with cisplatin (≥50 mg/m²) for the first time, age between 20 and 75 years, and with Eastern Cooperative Oncology Group performance status of 0–2. Eligible patients were randomly assigned (1:1) to receive either oral olanzapine 5 mg or placebo once daily on days 1–4 combined with aprepitant, palonosetron, and dexamethasone (dosage based on the standard antiemetic therapy against highly emetogenic chemotherapy). Patients were randomly assigned to interventions by use of a web entry system and the minimisation method with a random component, with sex, dose of cisplatin, and age as factors of allocation adjustment. Patients, medical staff, investigators, and individuals handling data were all masked to treatment assignment. The primary endpoint was the proportion of patients who achieved a complete response, defined as absence of vomiting and no use of rescue medications in the delayed phase (24–120 h). All randomly assigned patients who satisfied eligibility criteria received a dose of cisplatin 50 mg/m² or more, and at least one study treatment, were included in efficacy analysis. All patients who received any treatment in this study were assessed for safety. This study is registered at UMIN Clinical Trials Registry, number UMIN000024676.

Findings

Between Feb 9, 2017, and July 13, 2018, 710 patients were enrolled; 356 were randomly assigned to receive olanzapine and 354 were assigned to receive placebo. All eligible patients were observed 120 h after cisplatin initiation. One patient in the olanzapine group and three in the placebo group did not receive treatment and were excluded from all analyses. One patient in the olanzapine group discontinued treatment on day 1 and was excluded from the efficacy analysis. In the delayed phase, the proportion of patients who achieved a complete response was 280 (79% [95% CI 75–83] of 354 patients in the olanzapine group and 231 (66% [61–71] of 351 patients in the placebo group (p<0·0001). One patient had grade 3 constipation and one patient had grade 3 somnolence related to treatment in the olanzapine group.

Interpretation

Olanzapine 5 mg combined with aprepitant, palonosetron, and dexamethasone could be a new standard antiemetic therapy for patients undergoing cisplatin-based chemotherapy.

Funding

Japan Agency for Medical Research and Development.

Introduction

Chemotherapy-induced nausea and vomiting is an unpleasant adverse event that can affect many patients. When not treated with antiemetics, the incidence of vomiting in patients treated with highly emetogenic chemotherapy exceeds 90%.¹ Currently, the standard antiemetic therapy for cisplatin—a highly emetogenic chemotherapy agent—involves triplet-combination therapy with a 5-hydroxytryptamine-3 (5-HT3) receptor antagonist, neurokinin-1 (NK1) receptor antagonist, and dexamethasone. However, the efficacy of this approach in the delayed phase (24–120 h after initiation of therapy with cisplatin) is insufficient.2, 3

Research in context

Evidence before this trial

We searched PubMed for articles published between January 1, 2000, and December 31, 2018, with the terms “CINV”, “highly emetogenic chemotherapy”, “HEC”, and “olanzapine”, with no language restrictions. Olanzapine has been investigated as an antiemetic agent because it suppresses various receptors associated with nausea and vomiting. American Society of Clinical Oncology and National Comprehensive Cancer Network guidelines recommend a combination of olanzapine 10 mg with the 5-hydroxytryptamine-3 receptor antagonist, neurokinin-1 receptor antagonist, and dexamethasone, for patients treated with highly emetogenic chemotherapy including cisplatin. In these guidelines, the recommended dose of olanzapine was 10 mg, based on the study by Navari and colleagues. However, several guidelines suggested that a dose of 5 mg should be considered in patients at risk of sedation. We previously did a randomised phase 2 study comparing 5 mg and 10 mg olanzapine combined with standard antiemetic therapy in patients receiving cisplatin. In the delayed phase (24–120 h after initiation of highly emetogenic chemotherapy) the proportion of patients achieving complete response were 78% in the 10 mg group and 86% in the 5 mg group. The most common treatment-related adverse event was somnolence (53% in the 10 mg group vs 45% in the 5 mg group).

Added value of this study

To our knowledge, the J-FORCE study was the first randomised, double-blind, placebo-controlled, phase 3 study to show that olanzapine 5 mg plus triplet-combination therapy results in a significant improvement compared with standard care (triplet-combination therapy) in the proportion of patients achieving complete response during the delayed phase, in patients treated with a cisplatin-based regimen.

Implications of all the available evidence

Our finding regarding the difference in complete response is clinically relevant as it exceeded the minimum difference of 10% for most efficacy assessments, which is the threshold recommended by the Multinational Association of Supportive Care in Cancer/European Society for Medical Oncology (MASCC/ESMO) guideline. Our findings showed that olanzapine 5 mg combined with aprepitant, palonosetron, and dexamethasone could be a new standard antiemetic therapy in patients undergoing cisplatin-based chemotherapy.

Olanzapine is an antipsychotic drug that targets multiple receptors and acts as an antagonist against various substances, including dopamine, serotonin, adrenaline, histamine, and muscarine.4, 5, 6 Olanzapine has been investigated as an antiemetic drug because it is thought to suppress various receptors, including those for dopamine, serotonin, epinephrine, histamine, and muscarine. The guidelines established by the American Society of Clinical Oncology and National Comprehensive Cancer Network recommend a combination of olanzapine 10 mg with the aforementioned triplet-combination therapy (5-HT3 receptor antagonist, NK1 receptor antagonist, and dexamethasone) against highly emetogenic chemotherapy agents (HEC), including cisplatin.7, 8 However, these guidelines state that reduction of the dose of olanzapine to 5 mg should be considered for patients older than 75 years, and those who have excessive sedation while receiving olanzpine 10 mg.7, 8 Moreover, the guidelines established by the European Society for Medical Oncology and Multinational Association of Supportive Care in Cancer warn clinicians about excessive sedation following treatment with olanzapine 10 mg.⁹ Triplet-combination therapy is a standard antiemetic therapy for the prevention of chemotherapy-induced nausea and vomiting in patients receiving cisplatin-based chemotherapy. However, several studies that investigated this triplet combination therapy with olanzapine included a large proportion (60%) of participants treated with an anthracycline regimen.10, 11 Therefore, whether a four-drug combination therapy is effective for cisplatin-based regimens remains unclear, but we expected that olanzapine 5 mg would provide sufficient antiemetic efficacy for patinents receiving chemotherapy for the first time.

We have done three phase 2 studies investigating the efficacy and safety of the triplet-combination therapy with olanzapine 5 mg against chemotherapy-induced nausea and vomiting caused by cisplatin-based regimens.12, 13, 14 The four-drug combination therapy including olanzapine 5 mg showed a good antiemetic effect in a phase 2 study involving patients with gynaecological cancer (n=40);¹² in a single-centre, phase 2 study involving patients with lung cancer (n=30);¹³ and in a randomised, phase 2 study (n=153), which was planned to evaluate the efficacy and safety of two doses (10 mg and 5 mg) of olanzapine.¹⁴ In the latter study, complete response in the delayed phase was achieved in 59 (78%; 80% CI 70–84; p=0·010) of 76 patients in the 10 mg arm and 66 (86%; 72–91; p<0·001) of 77 patients in the 5 mg groups. Olanzapine 5 mg showed equivalent efficacy and a lower incidence of adverse events (including somnolence) than did olanzapine 10 mg.¹²

The objective of this phase 3 (J-FORCE) study was to test the superiority of olanzapine 5 mg compared with placebo plus triplet-combination therapy for the prevention of chemotherapy-induced nausea and vomiting caused by cisplatin-based chemotherapy in the delayed phase.